The difference between MS and ME

Hi Annesse, its is not proven that low glutathione does not lead to low neurotransmitters and hormones. In particular if the substance is a protein (some are) or if the substance requires a protein for synthesis or regulation (all do) then its dependent on correct functioning of that substance. Now glutathione is required for correct folding of very many proteins - and the larger the protein the higher the chance of this. If you were to assay these proteins, you would get normal or even high levels, despite that their functional capacity was decreased. I would be interested in other studies on glutathione depletion, to find out the neurotransmitter levels. From what I read of your commentary, your evidence backs glutathione being important this way.

I am very concerned about this for aconitase: let me use that as an example. Aconitase is not made by the mitochondria. It is a cell protein. It starts unfolded, and at some point has to be folded into its correct shape. I do not know if this is prior or after it enters the mitochondria - I suspect prior as the cell has extensive protein modification machinery. Glutathione is one of the substances used to do this folding by helping to create sulphide bridges. Once it has entered the mitochondria and is located correctly it can begin to convert citric acid. If its not folded correctly it can't. However, it also can't be shown to be deficient - there can be plenty of aconitase about, it just doesn't work if not folded. This might induce the cell to make more, and even more, leading to high aconitase levels, I don't know for sure - it would be interesting if someone could show elevated intracellular aconitase. That might be a sign of functional deficiency. Similarly high aconitase production might lead to higher protease synthesis to degrade the unfolded aconitase.

So in other words its an open question. You could be completely right, or partially right, or mostly wrong. We don't know yet. The only way we can tackle open questions is to do more research. That is why I am interested in your model.

I don't know about the circadian variation. My experience is with many urine organic acids tests, particularly the one offered by Genova Diagnostics, called the Metabolic Analysis Profile. There is also the Organix test offered by Metametrix, and the OAT offered by Great Plains Lab, and I have seen quite a few results of those, also.

These are run on first morning urine samples, so they reflect the metabolism that occurs during sleeping. The labs have reference ranges for the Krebs cycle metabolites, shown on the reports. What I'm referring to is the levels of these metabolites relative to their normal reference ranges. If citric acid is high relative to its normal mean value, while one or both of the following two are low relative to theirs, I interpret this as a partial block of aconitase. Of course, in doing this, I am relying on the labs to have accurate reference ranges for these metabolites, and one could question that, because these specialty labs often just base these ranges on a collection of samples people have sent them, and of course, most who send in samples to them are probably ill with some disorder, or they would not to testing. Nevertheless, I think this does work.

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Hi Rich, most of my data came from urinary organic acid profiles too. It would be nice to see it from another analytical approach as confirmation. The early morning results often show elevated urinary citrate, but my understanding is late day results typically don't. This is why I suspect a circadian bias. Since those with ME or CFS often have circadian issues, I suspect, I don't know for sure, that this might account for some of the variation in results. Not every patient has a circadian rhythm in synch with the testing protocol.

I do not know if reference ranges matter that much. The relative trend is more important, in my view, than matching to specific reference ranges.

Doesn't NO rise in sleep? I don't recall for sure. This alone might explain some of the discrepancy, as NO is a temporary inhibitor of aconitase. The real question is why the aconitase can be blocked. I think aconitase misfolding is an important hypothesis for this, which means glutathione depletion is too, which bring us back to oxidative stress, methylation cycle, etc etc.

It is worth mentioning for some who might not be aware that data on cellular metabolites obtained by measuring cells, not urine, also shows an elevation of pre-aconitase metabolites vs. post-aconitase metabolites, and this data was part of why I developed my first model.

Bye
Alex

PS On proteases in CFS, the primary one that has been investigated over the years is elastase. Its nearly always elevated, but not univerally.

I don't expect that most researchers, pharmaceutical executives, or even medical professionals will acknowledge this evidence. There would be no monetary benefit. This information would devastate the economy of the richest most powerful people in the world. It would put untold numbers of researchers and medical personnel out of work. Their jobs and their livelihoods depend on not finding the answer. The evidence will be ignored, but it cannot be denied.

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Hi Annesse

The best way to get people to acknowledge the evidence you present and get debate amongst researchers and clinicians is to publish your arguments in an academic journal. I asked you before if you've done this - I assume not. Are you considering this?

My symptoms were gradual over a period of about 15 months. The fatigue was the very last symptom and the most life altering. I have always been an active person. Running was one of my passions. You had mentioned in a previous post about exercising. I was in a state of complete exhaustion and spent 16 hrs a day in bed. However, I continued to move my lifeless body even if it were 10 minutes on my treadmill. Being physical also gave me a sense of purpose. If I lost that, the fight was over. I continue to walk 2 miles just about every day. It's not what it once was, but I'm am so grateful that I am able to experience that. I love to dance too and to me that is freedom. God Bless. Lee Ann

Hi Jenny and Lee Ann,
Jenny, I have been in contact with Dr. Woods (fibromyalgia researcher) and will let them take the lead on getting this information published in scientific journals. I think it would be difficult for a layperson such as myself to be taken seriously. Not that I wouldn't love to do it, but I just don't have the time to devote to getting it accomplished.
Lee Ann, I am so glad you are finding joy in the things you CAN do. I love to dance too.

Hi Rich, I think this information will clarify the discussion we had on gout and MS. I started this discussion by showing lupus patients lack the enzyme DNase 1. DNase 1 is a protease that breaks down DNA and proteins.The following information shows that uric acid is the final break down product of DNA.

Hi Rich, I think this information will clarify the discussion we had on gout and MS. I started this discussion by showing lupus patients lack the enzyme DNase 1. DNase 1 is a protease that breaks down DNA and proteins.The following information shows that uric acid is the final break down product of DNA.

It's good to hear from you again. It's true that uric acid is the final breakdown product of the purines, which are a component of DNA.

I don't mean to be contrary, but it's not true that Dnase1 is a protease. It is actually an endonuclease. It does break down DNA, but it does not break down proteins. Here is a reference on DNase1 from the OMIM database: http://omim.org/entry/125505

I continue to believe that you have a plausible hypothesis for the treatment of lupus by sauerkraut, and I also think it is a plausible hypothesis for the treatment of other disorders that are truly autoimmune. I continue to maintain that ME/CFS is not an autoimmune disorder.

I have read most of your book. I have been quite swamped lately by requests for help on individual cases, and am not able to keep up with them. I would like to be able to give you some detailed comments on your book, but have not been able to take the time to put them together. I think that some of your ideas have merit, but unfortunately they are mixed together with some statements in the book that are just not true, and I think this will subject your book to rejection by some people, which I would not like to see happen.

I am currently at the annual meeting of the Orthomolecular Health Medicine Society, in San Francisco. At lunch today I shared your name and the name of your book with Dr. Michael Schachter, who is interested in enzymes in the treatment of cancer. He wrote it all down. He thought that your basic idea is plausible, too.

I appreciate your feedback Rich. I do think though that I will stand my ground on DNase 1. Although please understand I am not saying it is simply a lack of DNase 1 that causes autoimmune disease. And I do include CFS under that umbrella, because I believe we have redefined what is actually taking place in autoimmune disease. It is not a random attack on healthy body tissues, but rather an immune system response to improperly made peptides and improperly broken down DNA and proteins as researchers have discovered in lupus, rosacea and diabetes for instance. The other factor being dysregulated TNF. I just posted a study on another thread to demonstrate CFS patients have dysregulated TNF. The spinal tap studies in CFS also found a protease imbalance and amyloids. So, if under the new understanding of what is really taking place in autoimmune disease, I do believe CFS has been shown to be a part of the same pathway. That is why, in the end, we are not able to find any differences between CFS and MS. Or why the spinal tap studies found 732 identical abnormal proteins in CFS, Fibro, and GWS.

Back to DNase 1. Here is a quote from the Department of Biochemistry. "DNase 1 as a digestive enzyme that is physiologically regulated is poorly understood. DNase 1 is mainly responsible for the digestion of dietary DNA before it can be absorbed into the body."

We have been told for a very long time indeed that the immune system was attacking normal healthy tissue for no reason. Researchers from around the world are now realizing that this is not the case. We do not understand the full extent of what DNase 1 does in the body, as the Department of Biochemistry states. Regardless of this, I state in my book, it is DNase 1 and protease that are lacking. It is the inability to digest DNA AND proteins that is the problem.

Solving a mystery, such as why in a review of 20 million patient records MS patients do not get gout, is just more evidence we have found the source of these diseases. We can trace every symptom of CFS and every valid scientific finding of every autoimmune disease back to missing pancreatic enzymes in just the same way. How can anyone overlook that?

Thank you for your input, truly, though. I look forward to discussing this with you further.

Looks like the conference is right by Alta Plaza Park, one of the nicest parks in San Francisco - and a couple of blocks from where we currently live (will be moving soon though). With this weather you should try and enjoy the park as much as possible
cheers

It's good to hear from you again. It's true that uric acid is the final breakdown product of the purines, which are a component of DNA.

I don't mean to be contrary, but it's not true that Dnase1 is a protease. It is actually an endonuclease. It does break down DNA, but it does not break down proteins. Here is a reference on DNase1 from the OMIM database: http://omim.org/entry/125505

I continue to believe that you have a plausible hypothesis for the treatment of lupus by sauerkraut, and I also think it is a plausible hypothesis for the treatment of other disorders that are truly autoimmune. I continue to maintain that ME/CFS is not an autoimmune disorder.

I have read most of your book. I have been quite swamped lately by requests for help on individual cases, and am not able to keep up with them. I would like to be able to give you some detailed comments on your book, but have not been able to take the time to put them together. I think that some of your ideas have merit, but unfortunately they are mixed together with some statements in the book that are just not true, and I think this will subject your book to rejection by some people, which I would not like to see happen.

I am currently at the annual meeting of the Orthomolecular Health Medicine Society, in San Francisco. At lunch today I shared your name and the name of your book with Dr. Michael Schachter, who is interested in enzymes in the treatment of cancer. He wrote it all down. He thought that your basic idea is plausible, too.

I have just come across this thread and have spent the evening reading 17 pages so I will have to go back and re-read and absorb some more.

Q: Can you define inability to digest proteins/poor protein digestion?

Are you referring to one process in particular or the series of processes starting with insufficient HCL in the stomach through to absorption via epithelium and the proper ratio of good intestinal bactria or specifically to the lack of proteolytic enzymes from the pancreas that are needed to digest protein? Or is the latter dependent on all the former (plus more)??

Rich @#152 explains the chain but it all appears to start with insufficient HCL. If that is the case can we increase it naturally via methylation protocol (due to its impact on restarting glutathione) or by HCL supplements or both until sufficient is produced? 5MTHF will help heal the epithelium and the sauerkraut and other probiotics will help. All the conditions referred to above seem to share IBS and fermented vegetables can only be of benefit.

Ok, so what you're saying - if I understand you correctly - is that avoiding enzyme inhibitors (by adopting an organic paleo diet) is the best way to improve protein digestion?

A paleo diet, high in vegetables, is likely more alkalizing than the standard high grain/carb western diet. At the same time, as you said, enzymes need HCL to work. How does this tie together?

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And at Post 141: Annesse, it is an interesting theory you have. Do you have any thoughts of enhancing the activity of DNase 1? I believe many CFS sufferers (including me) have already tried supplementing pancreatic enzymes without success.

Annesse

Are you able to comment on the above two posts please?

I apologise if you have and I missed it as I have just digested 17 pages at once.

Also at post #90 you say 'If you lack optimum acidity from inadequate digestion of protein, you will not have enough ionized calcium. In either case, you are a candidate for arthritis."

I have just come across this thread and have spent the evening reading 17 pages so I will have to go back and re-read and absorb some more.

Q: Can you define inability to digest proteins/poor protein digestion?

Are you referring to one process in particular or the series of processes starting with insufficient HCL in the stomach through to absorption via epithelium and the proper ratio of good intestinal bactria or specifically to the lack of proteolytic enzymes from the pancreas that are needed to digest protein? Or is the latter dependent on all the former (plus more)??

Rich @#152 explains the chain but it all appears to start with insufficient HCL. If that is the case can we increase it naturally via methylation protocol (due to its impact on restarting glutathione) or by HCL supplements or both until sufficient is produced? 5MTHF will help heal the epithelium and the sauerkraut and other probiotics will help. All the conditions referred to above seem to share IBS and fermented vegetables can only be of benefit.

Thank you. I have enjoyed this thread very much.

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Hi Topaz,

I am referring to the entire process of digestion. The entire GI tract needs to be addressed in order to restore the body's ability to properly digest proteins. There is most likely an overgrowth of pathogenic bacteria and yeast, loss of intrinsic factor, insufficient HCL, and lack of pancreatic enzymes.

Here is a study that found significant decreases in the proteinogenic amino acids.(amino acids which can be found in proteins) The study also states, "Several studies have suggested that disturbances in amino acid homostasis occur in CFS"

The study also found a "significant decrease in red cell distribution" and "succinic acid". Both of these findings are consistent with lack of B12. B12 is responsible for for the conversion of odd chain fatty acids into succinate. B12 is only found attached to dietary animal proteins and I have posted studies to show that without pancreatic protease, you would not be able to bind or transport vitamin B12. These same protease digest dietary proteins, so this is strong evidence that we are lacking these enzymes.

I personally don't believe any attempt to to fix the GI tract through supplementation will restore your body's ability to digest proteins. I have posted studies that show supplementation with amino acids,for instance, led to an increase in disease symptoms. They are just the components of proteins and if someone has lost the ability to digest proteins, they would not be helpful and may, in fact,lead to more harm. If you are unable to bind and transport vitamin B12 because you have lost protease will you successfully be able to circumvent the body's design and restore the lack of cellular B12 by taking supplements? Or will you cause yourself a great deal more harm? The study I posted from Norway found a 38% increased risk of cancer by taking B12 and folic acid supplements. If this is something you are unsure of, I would err on the side of caution. This is a huge risk to take. And in my opinion, completely unnecessary . If you work on healing your GI tract and give your body the nutrients it was designed to have in the form it was designed to use them in, it will do the rest. I know you have some more questions, and I can address those in my next post.

Can I add one more? lol! At post #173 you say "If you are unable to bind and transport vitamin B12 because you have lost protease will you successfully be able to circumvent the body's design and restore the lack of cellular B12 by taking supplements? " Does this apply to sublingual or iv B12?

Can I add one more? lol! At post #173 you say "If you are unable to bind and transport vitamin B12 because you have lost protease will you successfully be able to circumvent the body's design and restore the lack of cellular B12 by taking supplements? " Does this apply to sublingual or iv B12?

I wanted to make an additional comment on the study I just posted. The researchers state in the study,"The majority of studies, including the present investigation, have noted reductions in urine and plasma amino acid levels in patients with CFS compared with healthy controls."

Here is a study on MS and vitamin B12. There are many studies that show MS patients lack B12, but as this study states, "Serum (blood) levels of the vitamin are unrelated to the course or chronicity of the disease. Moreover, vitamin B12 does not reverse the associated macrocytic anemia nor are the neurological deficits of MS improved following supplementation with vitamin B12."http://www.ncbi.nlm.nih.gov/pubmed/8407160

Julie Stachowiak, a doctor with MS, wrote this in an article discussing the relationship between B12 and MS; "Studies have reported a significantly higher rate of vitamin B12 deficiency in people with MS than in people without MS, which is suspected to be due to problems with BINDING AND TRANSPORT." That is specifically what protease do with B12; they bind and transport it.

A paleo diet would not provide you with the enzymes necessary to digest proteins, nor would it effectively heal your GI, or restore your HCL and intrinsic factor. Pathogenic bacteria and yeast need to be addressed also and a diet of this type would not do that. If you eat proteins that you are unable to digest, they will cause an immune response. This is not a minor event, it can be life threatening. Here is a picture of undigested protein and DNA in a lupus patients bloodstream. The immune system forms NETS around the DNA and protein and these NETS can become lodged in organs and tissues, leading to organ failure. The last paragraph states lupus patients lack the enzyme DNase 1. http://www.sciencedaily.com/releases/2010/05/100503161423.htm

Julie Stachowiak, a doctor with MS, wrote this in an article discussing the relationship between B12 and MS; "Studies have reported a significantly higher rate of vitamin B12 deficiency in people with MS than in people without MS, which is suspected to be due to problems with BINDING AND TRANSPORT." That is specifically what protease do with B12; they bind and transport it.

Ok I think that clarifies my query. Protease is required to bind and transport B12. I did not know if sublingual or IV B12 circumvented the problem but it appears that once we get B12 into the bloodstream (half the equation for those that are unable to convert B12 during the digestive process) it still needs protease.

Is it protease that that enables the B12 to pass the blood brain barrier (BBB)? Or is there another process required also?

A paleo diet would not provide you with the enzymes necessary to digest proteins, nor would it effectively heal your GI, or restore your HCL and intrinsic factor. Pathogenic bacteria and yeast need to be addressed also and a diet of this type would not do that. If you eat proteins that you are unable to digest, they will cause an immune response. This is not a minor event, it can be life threatening. Here is a picture of undigested protein and DNA in a lupus patients bloodstream. The immune system forms NETS around the DNA and protein and these NETS can become lodged in organs and tissues, leading to organ failure. The last paragraph states lupus patients lack the enzyme DNase 1. http://www.sciencedaily.com/releases/2010/05/100503161423.htm

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How do you restore HCL? Via methylation (to stimulate glutathione production)?... but doesnt lack of protease impede that process (at least the B12 part of that process)??? The folate (5 MTHF) will assist in epithelium healing.

Paleo may not provide the enzymes or restore HCL but it can heal GI, restore beneficial intestinal flora and address yeast (if you are referring to Candida by yeast) via probiotics (sauerkraut and other fermented vegetables and kefir etc) and by not feeding the yeast by eliminating dairy (lactose) and fruit. A traditional diet with bone broth will help heal generally.

Am I correct in assuming that this process all hinges on restoring HCL as that in turn will have (positive) flow on effects down the GI and result in proper protease production?

I have read that zinc and Vit C can assist in production of HCL. Also that taking Betaine hydrochloride can often/sometimes stimulate increased production of HCL in those young enough.

You have alerted me to review a recent stool analysis report (which I will dig up tomorrow) which showed undigested or insufficiently digested protein. My practitioner then prescribed a supplement called Hydrozyme which comprises Betaine hydrochloride , glutamic acid and pepsin. I havent commenced taking this yet. I put the insufficiently undigested protein down to teh fact that I take 500mg of magnesium each night to counter IBS constipation and (incorrectly) concluded that it may have stimulated intestine motility before the food was sufficiently digested but now your last para in your post at 176 has me concerned. I will state that my practitioner vaguely agreed with me that this could be a possibility. I will read the link tomorrow as it is too late here right now. Even if that is a worst case scenario, autoimmune disease is linked to un/insufficiently digested proteins. Undigested food/protein is not visible to the naked eye in my case but was detected in lab tests. I will have to check the severity but I recall it was not at the high end of the range but above the reference range.

I have a referal for a h pylori (breath) test in the next couple of days as this is part of the equation. Luckily I have an obliging GP who is happy to assist with test requests even though I dont have the two typical symptoms for this.

Also, low HCL may likely allow pathogenic bacteria to pass through to the intestines instead of destroying it and that may lead to many of the other ME symptoms/complications.

I will investigate tomorrow what else can stimulate HCL production (although I suspect you already have the answer ). Perhaps probiotics but I suspect their benefit is principally in the next stage of digestion - the intestines.

Again BIG thanks and I very much look forward to continuing this dialogue.

Can I add one more? lol! At post #173 you say "If you are unable to bind and transport vitamin B12 because you have lost protease will you successfully be able to circumvent the body's design and restore the lack of cellular B12 by taking supplements? " Does this apply to sublingual or iv B12?

I wanted to make an additional comment on the study I just posted. The researchers state in the study,"The majority of studies, including the present investigation, have noted reductions in urine and plasma amino acid levels in patients with CFS compared with healthy controls."

Here is a study on MS and vitamin B12. There are many studies that show MS patients lack B12, but as this study states, "Serum (blood) levels of the vitamin are unrelated to the course or chronicity of the disease. Moreover, vitamin B12 does not reverse the associated macrocytic anemia nor are the neurological deficits of MS improved following supplementation with vitamin B12."http://www.ncbi.nlm.nih.gov/pubmed/8407160

Julie Stachowiak, a doctor with MS, wrote this in an article discussing the relationship between B12 and MS; "Studies have reported a significantly higher rate of vitamin B12 deficiency in people with MS than in people without MS, which is suspected to be due to problems with BINDING AND TRANSPORT." That is specifically what protease do with B12; they bind and transport it.

A paleo diet would not provide you with the enzymes necessary to digest proteins, nor would it effectively heal your GI, or restore your HCL and intrinsic factor. Pathogenic bacteria and yeast need to be addressed also and a diet of this type would not do that. If you eat proteins that you are unable to digest, they will cause an immune response. This is not a minor event, it can be life threatening. Here is a picture of undigested protein and DNA in a lupus patients bloodstream. The immune system forms NETS around the DNA and protein and these NETS can become lodged in organs and tissues, leading to organ failure. The last paragraph states lupus patients lack the enzyme DNase 1. http://www.sciencedaily.com/releases/2010/05/100503161423.htm

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This is an excerpt from the study you quoted:

"Here we show that serum endonuclease DNase1 is essential for disassembly of NETs. Interestingly, a subset of SLE patients sera degraded NETs poorly. Two mechanisms caused this impaired NET degradation: (i) the presence of DNase1 inhibitors or (ii) anti-NET antibodies prevented DNase1 access to NETs."

So nowhere is it stated that the patients lack Dnase 1. This is likely why supplying DNase out of a bottle doesn't work. Providing extra Dnase from foods are unlikely to help either, as the action of Dnase is blocked or impaired.

Another study found lower Dnase activity in SLEs, but no association with any disease parameters:

"No statistical relationship was found between DNase1 activity and disease evolution time, hypertension, presence of absolute or relative proteinuria, SLEDAI, new clinical manifestations, anti-Ro antibodies, anti-La antibodies, anti-RNP antibodies, anti-DNA antibodies, anti-cardiolipin antibodies, lupus anticoagulant, or with the treatment pattern received by the patients."

If you work on healing your GI tract and give your body the nutrients it was designed to have in the form it was designed to use them in, it will do the rest. I know you have some more questions, and I can address those in my next post.

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Annesse,

I agree with you that supplementation by and large is not necessary, that's my experience.
However, I'm not sure I understand whether you're proposing an alternative solution to solving the metabolic problems you have highlighted in various posts or just highlighting some of the issues that come up in CFS to support a new hypothesis about its causes etc.

I noticed that a couple of posts asked a similar question but got no answer. To rephrase, do you have an alternative solution to sort out the problems you highlighted?
If yes, can you describe it?

I think the B12 issue is best left to nature. What we know is protease are necessary for the metabolism of B12. The other thing we have seen is a huge possible increase in cancer and overall death risk from trying to resolve the lack of B12 through supplementation.Also, time and research has shown it has not been effective in reversing the course of these diseases. You also mention zinc. I have posted a study that shows heavy metal ions, such as zinc, have "chaperone" escorts to safely escort them through the interior of the cell and deliver them to the specific site where they are needed. Our cells need copper and other heavy metals, but when they are not properly chaperoned, they can destroy other cellular components. Again, best left to nature I think.

On the question of stomach acid,sauerkraut can raise stomach acid if it is too low and lower it if it is too high. It does this instantly. There is no need to look any further for supplements etc. The sauerkraut will also replenish the pancreas and help with the digestion of proteins. Plus, it can kill pathogenic bacteria and viruses. There isn't a drug or supplement that can do all of this and with no side effects.

Hi xrunner, I have a very comprehensive but simple approach to healing. Whole foods and whole herbs are an essential part of my recovery diet. It is one-third of my book though, so not practical or possible to detail it here. An important detail not to be overlooked though, would be that B12 is made my organisms in the soil. In order for our bodies to ingest B12, we need to eat animal protein that was raised on pasture. Ninety-five percent of our animals are raised on concrete. They contain little or no B12.